The refusal of allogeneic human blood and blood products by Jehovah's Witness (JW) patients complicates the treatment of life-threatening anemia. For JW patients, when hemoglobin (Hb) levels decrease beyond traditional transfusion thresholds (< 7 g/dL), alternative methods to allogeneic blood transfusion can be utilized to augment erythropoiesis and restore endogenous Hb levels. The use of erythropoietin-stimulating agents and intravenous iron has been shown to restore red blood cell and Hb levels in JW patients, although these effects may be significantly delayed. When JW patients have evidence of life-threatening anemia (Hb < 5 g/dL), oxygen-carrying capacity can be supplemented with the administration of Hb-based oxygen carriers (HBOCs). Although HBOCs are not Food and Drug Administration (FDA) approved, they may be obtained and administered with FDA, institutional review board, and patient approval. We describe a protocol-based algorithm to the management of life-threatening anemia in JW patients and review time to anemia reversal and patient outcomes using this approach.